Osteoporosis is an enormous public health problem that contributes to over 1.5 million fractures in the U.S. yearly. Current therapies modestly reduce fracture risk but no agent is able to fully restore skeletal integrity in most patients. Thus, there remains an urgent need for more effective treatments, particularly for those with severe disease. In the DATA study, we reported that when postmenopausal osteoporotic women are treated with the anabolic agent, teriparatide, along with the antiresorptive RANKL inhibitor, denosumab, bone mineral density, cortical bone microarchitecture, and estimated bone strength improve more than with either drug alone or with any available single agent. The superior efficacy of this combination approach appears to be related to denosumab?s ability to fully inhibit teriparatide?s pro- resorptive effects while still allowing for teriparatide-induced modeling-based bone formation. In a follow- up study currently underway (DATA-HD), we now demonstrate that using a higher dose of teriparatide in combination with denosumab increases bone density even more quickly and extensively than the regimen used in DATA, resulting in improvements in bone mass unachievable with even long-term use of any single agent. Given these extremely encouraging findings, it is now crucial that this approach be evaluated for its potential to reduce fractures in patients with severe osteoporosis. Such a demonstration will permit this regimen to be available as a treatment option for those patients at the highest risk of fragility fracture. This proposal aims to complete the planning of a double-blind placebo-controlled clinical trial that tests the hypothesis that in women with severe osteoporosis, 12-months of combined high-dose teriparatide and denosumab followed by 12-months of denosumab monotherapy will decrease fracture incidence substantially more than the current standard of care (oral alendronate treatment). To achieve this aim, we will collaborate an experienced coordinating center to identify optimal study sites, complete the detailed protocol and analysis plan, prepare an efficient budget, construct appropriate consent forms, and finalize a detailed and thorough manual of operating procedures. We will also prepare submissions to regulatory agencies and complete rigorous staff training. Given the unique potential of this novel therapeutic approach, the successful planning and completion of this comparative-efficacy trial has the potential to introduce a groundbreaking framework in osteoporosis therapy and substantially advance the treatment of patients with the most severe form of the disease.